The long-term goal of the proposed research is to define the metabolic causes of cancer cachexia by using 13 nuclear magnetic resonance spectroscopy (NMRS). Though weight loss continues to be one of the more common symptoms in cancer patients, the precise nature of metabolic alterations in cancer cachexia has yet to be defined. The paucity of information concerning the specific metabolic changes in the individual organ systems has been a significant obstacle to the effective treatment of patient wasting in cancer. However, with the recent application of NMRS to biological systems, it has become possible to examine tissue metabolism in intact organs. In our initial study of the livers of tumor rats, we found that hepatic uptake and metabolism of alanine were markedly increased, and the concomitant increase in glucose production was limited. We believe this indicates a less effective gluconeogenic process than that in the normals. That is, for a given quantity of glucose production, more substrates are required through lipolysis or protein catabolism, and energy expenditure may be increased during the process. This "ineffective" utilization of gluconeogenic substrates is probably a significant factor in the weight loss observed in cancer patients. We plan to delineate the "ineffectiveness" of glucose production from alanine, glycerol and lactate using NMRS, first in the perfused livers, then in the in situ livers, of tumor bearing rats. The substrate uptake, the Krebs cycle and the gluconeogenic pathway will be examined to define the specific site(s) of enzymatic alterations. Urea production will be monitored so that the energy requirement can be assessed. Accumulation of intracellular metabolites observed in NMR spectra will be confirmed by conventional analytic methods. Finally, the (in)effectiveness of glucose production will be defined in terms of the quantities of substrates and energy consumed, for a given amount of glucose produced.